Poor bioavailability of drugs has been a major limitation in the successful utilization of many therapeutic effective molecules. As it happens, most of these molecules are lipophilic in nature and tend to be poorly absorbed in the aqueous medium present in the Gastrointestinal (GI) tract. The problem of poor bioavailability is at times further compounded by a faster elimination rate which further reduces the efficiency of such molecules being used as a drug target of choice.
Curcuminoids, which are naturally occurring component in the common food spice turmeric (Curcuma longa), have been known to demonstrate wide range of therapeutic effects such as anti-inflammatory, anti-oxidant, anti-proliferative and anti-angiogenic. Curcumin is the principal curcuminoid present in turmeric. Chemically, curcumin is bis-α,β-unsaturated β diketone (commonly called diferuloylmethane, Formula 1). The other curcuminoids present in turmeric are, mainly, Bisdemethoxy curcumin and Demethoxy curcumin. In many cases, curcuminoid can be present solely or in combination with other active ingredients.

In addition to its application in a wide spectrum of therapeutic areas, curcuminoids are also found to be safe even in high doses. These features make curcuminoids a potential target for developing therapies across multiple disease segments. Curcuminoids, however, suffer from a major disadvantage which acts as a blockade in its wider acceptance as a drug moiety of choice. It is found that curcuminoids has a reduced bioavailability within the body. This has been attributed to the lipophilic nature of curcuminoids and hence its poor absorption in the GI tract, rapid metabolism and quick elimination from the body. It was found, for example, by Rabindranath et al, (Absorption and tissue distribution of curcumins in rat. Toxicology, 1980 16(3), 259-265) that after oral administration of 400 mg of curcumins to rats, no curcumin was found in heart blood whereas a trace amount was found in the portal blood from 15 minute to 24 hour after the administration of curcumin.
Oral administration is regarded as the preferred route of drug intake offering numerous advantages including convenience, ease of compliance, potential for availability to large patent population and cost effectiveness. Thus oral bioavailability is a key factor in lead selection and development of new drugs. Poor oral bioavailability affects the drugs performance and leads to inter and intra patient variability. A number of chemotherapeutic as well as chemopreventive agents suffer from poor oral bioavailability rendering them unsuitable for oral delivery. Oral bioavailability depends primarily on—Drug permeability, Aqueous solubility, Dissolution rate, Presystemic metabolism, First-pass metabolism and Susceptibility to efflux mechanisms. Of these low permeability and poor solubility are the most common causes of poor oral bioavailability.
The advances in understanding the cause of poor bioavailability have led to significant improvements in the design of technologies to combat these deficiencies. The strategies to improve oral bioavailability can be grouped into three main groups comprising: Pro-drugs and drug conjugates, Medicinal chemistry and Formulation design. The present invention proposes the application of formulation design to enhance the oral bioavailability of selected drug candidate.
Formulation Design is often the route of choice for modifying the oral bioavailability of drugs as it offers a low cost and rapid solution to these problems particularly for drug already in the market. As opposed to pro-drug and medicinal chemistry approaches, Formulation Design does not require chemical modification of the drug or creation of New Chemical Entities. This provides considerable advantage in terms of reduced cost and development timeline. Poor aqueous solubility and dissolution rate frequently affect the oral performance of drugs. This issue has been successfully addressed in the art by using techniques such as, Co solvents, Micronization, Solid dispersions, Surfactants, Nano-Suspensions, Micro emulsions and Self Emulsifying Drug Delivery Systems (SEDDS).
Pre-formed Emulsions/Phospholipid complexes containing the lipophilic entity have been a tried and tested method to achieve a better solubility and absorption. This generally involves forming ‘Lipids micelles’ of the lipophilic entity with the help of suitable surfactant(s). Such micelles are then delivered as such at the absorption site. US Patent Publication US 20090324703 discloses one such curcuminoid-lipid micelles, wherein and the composition is provided as a microemulsion or solid lipid nanoparticles (SLN). Such microemulsion or SLN, no doubt, improved the absorption rate of the lipophilic moieties at the absorption site but nevertheless were only marginally better. A study by Suresh et al, (Studies on the in vitro absorption of spice principles-curcumin, capsaicin and piperin in rat intestine. Food Chem. Toxicol. 2007, 45 (8), 1437-42) showed that the absorption of curcumin when present as micelles increased was 56% as compared to 47% when present in a free form.
The advent of the Self Emulsifying Drug Delivery Systems (SEDDS) technique witnesses a marked improvement in the bioavailability of the lipophilic moieties. SEDDS comprise of an isotropic mixture of drug, oil, surfactant and/or co-solvents which upon oral administration gets emulsified in the aqueous media in the GI tract. The distinguishing feature of SEDDS is its ability to emulsify spontaneously to produce fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation. The resulting oil-in-water emulsion is thermodynamically stable due to the relatively small volume of the dispersed oil phase, the narrow range of droplet size distribution and the polarity of the oil droplets (Groves M J, Degalindez D A, The self-emulsifying action of mixed surfactants in oil, Acta Pharm Suec, 13, 1976, 361-372). The oil-in-water emulsion shows higher absorption in the GI tract. This approach has found a general acceptance for the lipophilic drugs that suffer from poor absorption rates. The SEDDS approach is being successfully followed in commercially available formulations containing cyclosporin A, ritonavir and squinavir.
The success of the self emulsifying technique in increasing the bioavailability of the drug depends on the oil-surfactant pair, surfactant concentration and the temperature at which self emulsification occurs. It is also widely understood that the droplet size also plays a key role in determining the absorption rate and hence the overall bioavailability of the drug molecule, as a small droplet size provides a large interfacial area for its absorption.
With the recent developments in nanotechnology, oil droplets of nano dimensions have been achieved. These nano sized oil droplets are more effective in increasing the bioavailability of the drug molecule, courtesy their size. These drug delivery systems are called Self Nano Emulsifying Drug Delivery System (SNEEDS). SEDDS now represent a broad category typically encompassing emulsions with a droplet size ranging between a few nanometers to several microns, while SNEDDS is used specifically where oil droplets are below 150 nm in size.
WO2008154705 discloses a curcumin based pre formed nanoemulsion for targeted delivery of a nano-shell containing the active ingredient. The '705 published application, however, does not contemplate any use of a self emulsifying drug delivery system.
WO2010010431 discloses a self nano emulsifying curcuminoid formulation. The '431 publication discloses use of surfactants that invariably cause the active ingredient, curcuminoid, to precipitate out of the aqueous medium even after half an hour of formation of the self emulsifying formulation. To combat this, the '431 publication further teaches the use of a polymeric molecular aggregation inhibitor, specifically Hydroxypropyl methyl cellulose (HPMC), in the formulation. As is widely known in the art, adding HPMC has its own disadvantages, prominent being the tendency of undissolved HPMC in an aqueous medium to form lumps. The undissolved HPMC is present in the medium even after protracted periods of agitation, thus the problem of lump formation poses a serious risk to the stability of the formulation. The formulation of '431 publication, thus, suffers from an inherent disadvantage of their choice of surfactant and then adding an extra additive to address that disadvantage.
It is, therefore, a need in the art to develop a self emulsifying curcuminoid composition which has an enhanced drug loading ability as well as an increased bioavailability and better stability. Further, a self emulsifying curcuminoid composition of such nature must also be able to address the lacunas present in the existing art, specifically as elaborated in the preceding paragraphs. Further, it would be desirable that such a composition is based on creating a nano emulsion at the absorption site so as to markedly increase the absorption efficiency.